Process for obtaining d(-)-alpha-hydroxy-beta, beta-dimethyl-gamma-butyrolactone



United States Patent PROCESS FOR OBTAINING D()-a-HYDROXY-B,B-DIMETHYL-y-BUTYROLACTONE Charles 0. Beckmann, Bayville, and Howard C.Klein, Brooklyn, N.Y., and Richard Griflith, Middletown, N.J., assignorsto Nopco Chemical Company, Harrison, N.J., a corporation of New JerseyNo Drawing. Filed June 19, 1958, Ser. No. 742,996

23 Claims. (Cl. 260-343.6)

The present invention relates to a process for directly obtaining D-a-hydroxy- 8,fl-dimethyl-'y-butyrolactone from a racemic mixture ofa,'y-dihydroxy-fl,p-dimethyl butyramide or from a racemic mixture ofa-hydroxy-;8,fi dimethyl-y-butyrolactone.

The material a,' -dihydroxy-fi,fl-dimethylbutyramide, also referred toas pantamide, is of great utility in the preparation of pantothenic acidas well as derivatives thereof, e.g., calcium pantothenate. One of theprocedures which utilizes pantamide has involved the preparation ofa-hydroxy-,B,p-dimethylw-butyrolactone also known as pantolactone andthereafter converting it to pantamide by treatment with ammonia.Subsequently, the pantamide is reconverted to the lactone. Suchprocedure is carried out in order to purify the lactone. Since thepantothenic acid or a derivative thereof which would be obtained fromthe L(+)-pantolactone has no physiological activity, it is necessaryduring the process for the preparation of pantothenic acid to resolvethe lactone in order to obtain the desired D()-optical isomer. Theresolution of racemic pantolactone is required whether or not theprocess makes use of the intermediate pantamide. This heretofore hasbeen accomplished by treating racemic pantolactone with l-brucine. TheD()-isomer of the lactone is recovered as the brucine complex which bysubsequent treatment with a base followed by relactonization with anacid frees the D -isomer.

In copending application Serial No. 742,979, Klein, Kapp and Griflith,filed concurrently herewith, a greatly improved procedure is disclosedand claimed for the preparation of D(--)-pantolactone from racemicpantamide. In brief, racemic pantamide in an inert solvent, preferablymethanol, is treated with l-brucine at elevated temperatures. There isformed as reaction products a complex of D()-pantolactone and l-brucineand a complex of L(+)-pantolactone and l-brucine. Because of thedifference in solubilities of these two complexes, the former may beprecipitated from solution while the latter remains in solution. In thismanner, the complex of the D()-pantolactone and l-brucine is recoveredfrom which free D()-pantolactone may be obtained by treatment with abase followed by relactonization with an acid. The D(-)-pantolactone isthereby obtained in excellent yields and high purity. However, it mustbe realized that only a maximum yield of one-half mol ofD()-pantolactone can be obtained from one mol of the starting material,racemic pantamide. This is because only the D(-) enantiomorph present inracemic pantamide is utilized to prepare D(-)-pantolactone sincepantothenic acid or any derivative thereof obtained fromL(+)-pantolactone lacks physiological activity.

Accordingly, it is an object of the present invention to obtainD()-u-hydroxy-fl,fl-dimethyl-y-butyrolactone in an improved and moredirect manner than has been heretofore accomplished. It is a furtherobject to obtain D( )-pantolactone in higher purity and larger yieldswhen compared with prior art procedures. It is a more however, that thedetailed description and the specific v examples do not limit theinvention, but merely indicate the preferred embodiments thereof sincevarious changes and modifications within the scope of the invention willbecome apparent to those skilled in the art.

The above and other objects have been unexpectedly accomplished in thefollowing manner. Racemic pantamIde or racemic pantolactone in an inertsolvent, preferably methanol, is treated with l-brucine and aracemization agent at elevated temperatures. There is formed as areaction product, when either of said starting materials is utilized, apreponderance of a complex of D(--)-. pantolactone and l-brucine. TheD(-)-pantolactone may then be recovered by treatment with a basefollowed by relactonization with an acid. Thus by following theprocedure herein, excellent yields of highly pure D()- pantolactone maybe obtained in yields approaching of theory, said yields being basedupon all of the starting material i.e., racemic pantamide or racemicpantolactone.

According to theteachings of copending Serial No. 742,979 it is known toobtain D()-pantolactone directly from racemic pantamide. It is furtherknown to resolve racemic pantolactone with l-brucine. Racemization ofphysiologically inactive pantolactone with variouslracemization agentsor catalysts has also been taught by the art. However, it was unexpectedto discover that L(+)-pantolactone contained in theL(+)-pantolactonel-brucine complex could be preferentially racemized toyield D(-)-pantolactone l-brucine complex leaving the l-brucine moietyunaffected. Moreover, D(-)-lactone l-brucine complex already presentplus that amount formed as a result of the above racemizationsurprisingly remains unaffected by the racemizing agent and this complexdoes not limit the extent of racemization of the L(+)-pantolactonel-brucine complex. Hence, racemization of L(+)-pantolactone l-brucinecomplex con-' tinues until virtually all of the starting material i.e.,racemic pantamide or racemic pantolactone has been con verted into thedesired diasterioisomeric D(--)-pantolactone l-brucine complex.

The advantages of such a procedure, wherein we are able in a single stepto obtain directly from racemic pantamide or from racemic pantolactoneextremely high yields of the D(-)-pantolactone l-brucine complex bytreatment of said starting material with both a resolving agent and aracemization agent simultaneously are many fold and substantial. Theproductivity of each production unit is greatly increased, an objectivetoward whichall industries strive. Moreover, further economies aregained by the incorporation into a single operation the previouslyessential and separate steps of resolution and racemization. Heretoforea common feature of industrial resolution procedures involved first theresolution of racemic pantolactone with l-brucine. Thereafter, thephysiologically inactive enantiomorph, L(+)-pantolactone, was recoveredfrom its brucine complex by means of alkali extraction which removed thepantolactone as the sodium salt in the presence of an organic solventwhich dissolved the brucine. Then, the pantoate was relactonized withacid, followed by the steps of neutralization, extraction, drying, etc.Finally, the L(+)-pantolactone was subjected to various more or lessinvolved racemization procedures, many of which called for distillationtechniques or extraction techniques for recovery of the racemizedpantolactone. Thus, the present invention eliminates previouslynecessary materials and prc- Patented Jan. 10,

viously necessary steps. The present invention will also bring aboutmore satisfactory working conditions through reduction in the handlingof materials which are always a potential health and safety hazard, inparticular, the alkaloid brucine.

The quantity of l-brucine utilized in the reaction may be from about 1.0to 1.1 mols of l-brucine per mol of racemic pantamide or racemicpantolactone. Generally it is preferred to employ about a 5% to excesse.g., 1.1 mols of l-brucine. It is true that this quantity of 1- brucineis considerably in excess of the quantity utilized in copending SerialNo. 742,979. However, because a much larger yield of D()-pantolactonel-brucine complex is obtained, the cost of the larger quantities of 1-brucine called for herein becomes relatively insignificant. Althoughreaction is preferably brought about at the reflux temperature of thereaction mixture other temperatures of from about 40 C. up to the refluxtemperature may be used. Of course, the lower the temperature, thelonger the reaction time will be. Generally, the reaction time will befrom about 3 hours to 48 hours. At reflux temperature, a preferredreaction time of from about 16 to 22 hours is used when racemicpantamide is the starting material. When racemic pantolactone is thestarting material, at reflux temperature, the reaction time ispreferably from about 3 to 8 hours. In other words, a longer time forthe process is needed when racemic pantamide is the starting material.

The selection of a solvent may be made from any number of liquid organicmaterials which are inert with respect to the reactants i.e., theracemic starting materials and the l-brucine and the racemizationagents. The racemic pantamide or racemic pantolactone and l-brucine maybe dissolved or suspended in the solvent. Suitable solvents aremethanol, isopropanol, ethanol, etc. It is preferred that the solventand in fact the entire reaction mixture be free from water. The quantityof solvent employed is usually from about 2.5 to 5 parts thereof perpart by weight of l-brucine used.

Concerning the racemization agent we prefer to use from about 3% to 26%by weight based upon the weight of racemic pantamide or racemicpantolactone. However, best yields are obtained when the racemizationagent is present in an amount of from about 10% to 20% by weight of saidracemic pantamide or racemic pantolactone. Suitable racemization agentshave been found to be alkali metal and alkaline earth metal alcoholatesin which the alcohol portion has been derived from a lower aliphaticalcohol containing from 1 to about 4 carbon atoms. Such alcoholates aree.g., sodium methoxide, sodium ethoxide, sodium isopropoxide, magnesiummethoxide, and magnesium isopropoxide. Also useful as racemizationagents are the following: aluminum isopropoxide; alkali metal silicates,e.g., sodium silicate, sodium orthosilicate, sodium metasilicate,potassium silicate, potassium tetrasilicate and alkali metal carbonatessuch as sodium carbonate and potassium carbonate.

It it is desired to racemize the complex of L(+)-pantolactone l-brucinealone, any of the preceding racemizing agents may be used. They may bepresent in an amount of from 3% to 26% by weight based upon the weightof the lactone moiety of the complex. Temperatures of from about 40 C.up to the reflux temperature may be used and the reaction time may befrom 3 to 48 hours. In other words, reaction conditions will correspondto those used when both resolution and racemization are carried out uponracemic pantolactone or racemic pentamide.

For a fuller understanding of the nature and objects of the invention,reference may be made to the following examples which are given merelyto illustrate the invention and are not to be constructed in a limitingsense. The percent yields where reported are based upon the totalquantity of starting material i.e., racemic pantamide or racemicpantolactone.

4 Example] This example is included to demonstrate the unexpectedracemization of L(+)-pantolactone l-brucine complex toD('+)-pantolactone l-brucine complex.

26 grams of L(+)-pantolactone (0.2 mol) were dissolved in 185 ml. ofmethanol and thereafter admixed with 78.8 grams of l-brucine. Thismixture was refluxed for 3 hours and allowed to stand overnight. In thismanner, the brucine complex was formed. The solution was then treatedwith 5.4 grams of sodium methoxide (0.1 mol) and refluxed. A precipitateof D(-)-pantolactone l-brucine complex began to form in about 10minutes. Refiuxing was continued for 3 hours during which time thecomplex continued to precipitate out thereby forming a slurry.Thereafter, the slurry was cooled to room temperature, centrifuged anddried. In this manner, 71.5 grams of D()-pantolactone l-brucine complex(68% of theory) were obtained having a melting point at 202 to 205 C. Asecond crop of complex weighing 14.26 grams and melting at 177 to 179 C.was obtained from the mother liquor.

Example II 26 grams of racemic pantolactone (0.2 mol) and 1.1 grams ofsodium methoxide (0.02 mol) contained in 30 ml. of methanol, were addedto 78.8 grams of l-brucine (0.2 mol) contained in 156 ml. of methanol.The resulting mixture was refluxed for 2 /2 hours and allowed to standat room temperature overnight. After centrifuging, washing with methanoland drying, 65.4 grams of D()- pantolactone l-brucine (62% of theorybased upon all of the racemic pantolactone) melting at 203 to 206 C.were obtained. Upon chilling the mother liquor, 13.46 grams ofadditional complex melting at to 177 C. were obtained.

D(-)-pantolactone was obtained from the complex in the following manner.The 65.4 grams of complex obtained above were treated with 65 ml. ofchloroform and 5.35 grams of sodium hydroxide contained in 35 ml. ofwater for one hour at room temperature. The aqueous layer was extracted6 times with 20 ml. portions of chloroform in order to remove thebrucine. The sodium pantoate contained in the aqueous layer wasrelactonized by treatment with 11 ml. of concentrated hydrochloric acid.Extraction of the crude D(-)-panto1actone yielded 15.29 grams. Thismaterial was then recrystallized from 7 ml. of methyl isobutyl ketoneand 7 ml. hexane thereby yielding 9.77 grams of D()-pantolactone (37% oftheory). The ((1) was 44.8.

Example 111 To 65 grams of racemic pantolactone (0.5 mol) contained in60 ml. of methanol, 2.75 grams of sodium methoxide were added. Theresulting solution was then added to 197 grams of l-brucine (0.5 mol)contained in 390 ml. of methanol. After 16 hours of refluxing, the reaction mixture was cooled down and 161.4 grams of D()- pantolactone1-brucine complex (61.5% of theory) were recovered. The complex meltedat 202 to 207 C. Chilling the mother liquor to -12 C. yielded anadditional 47.4 grams of complex melting at 169 to 173 C.

Example IV 66.5 grams of 97.6% pure racemic pantolactone (0.5 mol)contained in 40 ml. of dry methanol were added during the course of /2hour to a refluxing solution of 200 grams of l-brucine (0.5 mol) and 12grams of sodium methoxide (0.22 mol) in 400 ml. of methanol. Refiuxingwas carried out for 3 hours with stirring. Thereafter, the slurry wascooled to room temperature, centrifuged and dried. In this manner, gramsof D()- pantolactone 1'-brucine complex (70% of theory based on all ofthe racemic lactone) were obtained having a melting point of 201 to 204C. A second crop from Example V This example is directed to a variationof our process in which racemic pantolactone is first resolved bytreatment with l-brucine. The remaining L(+)-pantolactone l-brucinecomplex is subsequently racemized in a manner similar to Example I. Thisvariant may also be applied when the starting material is racemicpantamide.

133 grams of 97.6% pure racemic pantolactone (1.0 mol) contained in 40ml. of dry methanol, which was prepared by distilling over sodiummethoxide, were added during 20 minutes to a refluxing solution of 200grams (0.5 mol) of l-brucine contained in 400 ml. of dry methanol. Afterminutes of refluxing the resulting slurry was cooled and centrifuged. Inthis manner 252 grams of crude D(-)-pantolactone l-brucine complex (48%of theory based on all of the racemic pantolactone) were obtained. Thecomplex melted at 201 to 204 C. This material was redigested with 375ml. of methanol for /2 hour at reflux temperature, cooled and filteredto yield 232 grams of purified complex (44% of theory based on all ofthe racemic lactone) melting at 203 to 206 C. The original mother liquorwas combined with the mother liquor from the redigested crude complexand treated anew with 100 grams of l-brucine (0.25 mol) contained in 200ml. of dry methanol. 250 ml. of the methanol were distilled ofl? and theresidue treated with 8 grams of sodium methoxide contained in 50 ml. ofmethanol at reflux temperature for 3 hours. In this manner a secondportion of complex weighing 120 grams (22.9% of theory) was filteredofi. It melted at 196 to 201 C. Redigestion of this material withmethanol yielded 99 grams (19% of theory) melting at 200 to 203 C. Tothe combined mother liquors were added 100 grams of l-brucine dissolvedin 200 ml. of methanol. This solution was concentrated to 300 ml. andrefortified with 5 grams of sodium methoxide contained in 50 ml. ofmethanol. After 6 hours of reflux, the resulting slurry was cooled andfiltered from which was obtained a third crop of D()-pantolactonel-brucine complex weighing 47 grams and melting at 186 to 196 C.Redigestion of this complex with methanol resulted in 22.7 grams ofpartially purified complex melting at 199 to 205 C. which amounted to4.3% of theory. Hence, the total quantity of D()pantolactone l-brucinecomplex isolated was 353.7 grams which was 67% of theory based upon allof the racemic lactone.

This complex was split by treatment with 360 ml. of chloroform and 31.6grams of sodium hydroxide contained in 220 ml. of water for one hour atroom temperature. The aqueous layer containing sodium pantoate wasextracted with chloroform to remove all of the 1- brucine, relactonizedwith hydrochloric acid and finally extracted with isopropyl acetate.79.6 grams of crude D(--)-pantolactone were thus obtained. The crude D()-pantolactone was recrystallized from a solution of 40 ml. methylisobutyl ketone and 40 ml. hexane to yield 53.0 grams ofD()-pantolactone (40.7% of theory) having a (a) =-48.6.

Example VI 400 ml. of methanol, 197 grams of l-brucine (0.5 mol) and17.7 grams (0.1 mol) of aluminum isopropoxide were refluxed for 3 hours.Thereafter 67.5 grams of 97.5% pure (0.5 mol) racemic pantolactonecontained in 20 ml. of methanol were added. Refluxing was then continuedfor 3 hours. After cooling and filtration, 196.7 grams ofD(-)-pantolactone l-brucine complex melting at 198 to 203 C. wererecovered. Redigestion of the complex with 200 ml. of methanol yielded195.6 grams of purified complex which amounted to 61% of theory basedupon all of the racemic lactone starting material.

Example VII 2.4 grams of magnesium turnings (0.1 mol) were con verted tomagnesium methoxide by refluxing overnight with 390 ml. of methanol. Tothe resulting magnesium methoxide in methanol, 197 grams of l-brucine(0.5

mol) were added and refluxing carried out. After three hours ofrefluxing, 66.5 grams of 97.6% pure racemic.

pantolactone contained in 40 ml. of methanol were added. After anadditional 3 hours of refluxing, the resulting slurry was cooled andfiltered thereby yielding 200.9 grams of crude D(-)pantolactonel-brucine complex melting at 197 to 205 C. The complex was purified byredigestion with 200 ml. of methanol. Upon recrystallization from themethanol, 154.9 grams of purified complex (59% of theory) were recoveredhaving a melting point of 201 to 204 C.

Example VIII 8.0 parts by weight of l-brucine were refluxed with crudeD(-)-pantolactone l-brucine complex were recovered. The complex meltedat 201 to 204 C. Upon redigestion with 11 parts by volume of drymethanol, 7.3 parts by weight of complex were obtained melting at 201 to204 C. Although this new melting point would indicate very littlepurification, considerable color was removed. The purified complex wassplit by treatment with 7.2 parts by volume of chloroform and a solutionof 0.63 part by weight of sodium hydroxide dissolved in 4.4 parts byvolume of water. The aqueous layer was extracted with 5 portions of 2.4parts by volume chloroform and subsequently relactonized with 1.5 partsby volume of 37% by weight aqueous solution of hydrochloric acid. Thisaqueous layer was neutralized to a pH of 5 with ammonium hydroxide andextracted twice with 2.2 parts by volume portions of isopropyl acetateand then with 5 portions of 1.6 parts by volume isopropyl acetate. Theextracts were combined and evaporated.

parts by volume of methyl isobutyl ketone and 875 parts by volume ofhexane yielded 1.39 parts by weight of D(-)-pantolactone (53.5% oftheory) having a Example IX 26 grams of L(+)-pantolactone dissolved in30 ml.

of methanol were added to a solution of grams of 1- brucine dissolved in250 ml. of methanol. After 15 minutes of reflux, 4 grams of sodiumsilicate which were pro-dried at 106 C. were added to the solution.Refluxing was continued for 23 hours. A precipitate began to form about4 hours after the silicate addition. After refluxing, the slurry Wascooled to 40 C., centrifuged and dried. In this manner, 45.5 grams ofD()-pantolactone l-brucine complex melting at 199 to 202 C. wererecovered. This weight has been corrected for the Weight of the sodiumsilicate which was collected with the product since it is insoluble inmethanol.

Example X a 26 grams of L(+)-pantolactone dissolved in 30 ml. ofmethanol were added to 80 grams of l-brucine dissolved in 220 ml. ofmethanol. The resulting solution was refluxed for 15 minutes. Thereafter4 grams of potassium= carbonate were added and refluxing continued. Thealmost clear solution began to precipitate white crystalline 1.8 partsby; weight of crude D()-pantolactone were recovered. Recrystallizationof this material from a solution of 875 v of D()-pantolactone l-brucinecomplex melting at 201 to 205 C. were recovered.

Example XI 29.4 grams of racemic pantamide, 80 grams of 1- brucine and150 ml. of methanol were refluxed together for minutes. Thereafter 5.4grams of sodium methoxide dissolved in 50 ml. of methanol were added tothe refluxing materials and refluxing was continued for 23 hours.Precipitation began in about /2 hour after the addition of sodiummethoxide. The slurry, after refluxing was discontinued, was cooled downto 40 C., centrifuged, washed with methanol and dried. In this manner71.5 grams of D()-pantolactone l-brucine complex were recovered whichamounted to 68% of theory based upon all of the starting material,namely, racemic pantamide.

Having thus described our invention, what we claim as new and desire tosecure by Letters Patent is:

1. A process for obtaining D()-ahydroxy-fl,B-dimethyl-'y-butyrolactonewhich comprises the steps of bringing into contact with each otherl-brucine and a racemic material selected from the group consisting ofracemic 01,7 dihydroxy 13,5 dimethylbutyramide and racemica-hydroxy-flp-dimethyl-y-butyrolactone in the presence of from about 3%to about 26% by weight of said racemic material of a racemization agentin methanol, recovering from the resulting reaction product a complex ofl-brucine D(-)-a-hydroxy-fi,;3-dimethyl- 'y-butyrolactone and freeingfrom said complex said D()-a-hydroxy-Bfi-dimethyl- -butyrolactone, saidracemization agent being selected from the group consisting of alkalimetal and alkaline earth metal alcoholates in which the alcohol portioncontains from one to about four carbon atoms, aluminum isopropoxide,alkali metal silicates and alkali metal carbonates.

2. A process for obtaining D(--)-a-hydroxy-p,p-dimethyl-'y-butyrolactonewhich comprises the steps of bringing into contact with each other fromabout 1 to 1.1 mols of l-brucine and one mol of a racemic materialselected from the group consisting of racemica,'y-dihydroxy-dfl-dimethyl butyramide and racemic a-hydroxy-13,;9-dimethyl-' -butyrolactone in the presence of from about 3% toabout 26% by weight of said racemic material of a racemization agent inmethanol, recovering from the resulting reaction product a complex ofl-brucine D(-)-a-hydroxy- 3,fi-dirnethyl'y-butyrolactone and freeingfrom said complex said D(-)-u-hydroxy-B,fi-dimethyl- 'y-butyrolactone,said racemization agent being selected from the group consisting ofalkali metal and alkaline earth metal alcoholates in which the alcoholportion contains from one to about four carbon atoms, aluminumisopropoxide, alkali metal silicates and alkali metal carbonates.

3. A process for obtaining D()-a-hydroxy-B fl-dimethyl-'y-butyrolactonewhich comprises the steps of bringing into contact with each other at atemperature of from about 40 C. up to the reflux temperature of thereaction mixture, a mixture of from about 1 to 1.1 mols of l-brucine andone mol of a racemic material selected from the group consisting of u,'-dihydroxy-fl,pdimethyl butyramide and racemic a-hydroXy-fi,B-dirnethyl-'y-butyrolactone in the presence of from about 3% to about 26% by weightof said racemic material of a racemization agent in methanol, recoveringfrom the resulting reaction product a complex of l-brucine D(--)-a-hydroxy-pfi-dimethyl- -butyrolactone and freeing from said complexsaid D(--)-u-hydroxy-B,B-dimethyl-y-butyrolactone, said racemizationagent being selected from the group consisting of alkali metal andalkaline earth metal alcoholates in which the alcohol portion containsfrom one to about four carbon atoms, aluminum isopropoxide, alkali metalsilicates and alkali metal carbonates.

4. A process for obtaining D()-a-hydroxy-fi,;3-dimethyl-'y-butyrolactonewhich comprises the steps of bringing into contact with each other at atemperature of from about 40 C. up to the reflux temperature of thereaction mixture, for about 3 to 48 hours a mixture of from about 1 to1.1 mols of l-brucine and one mol of a racemic material selected fromthe group of racemic a-v-dihydroxy-flfi-dimethyl butyramide and racemicahydroxy-[3,fi-dimethyl-'y-butyrolactone in the presence of from about3% to about 26% by weight of said racemic material of a racemizationagent in methanol, recovering from the resulting reaction product acomplex of l-brucine D(-- -a-hydroxy-;3,f3-dimethyl-'y-butyrolactone andfreeing from said complex saidD(--)-a-hydroxy-p,fl-dimethyl-'y-butyrolactone, said racemization agentbeing selected from the group consisting of alkali metal and alkalineearth metal alcoholates in which the alcohol portion contains from oneto about four carbon atoms, aluminum isopropoxide, alkali metalsilicates and alkali metal carbonates.

5. The process of claim 4 in which said racemic material is racemica,'y-dihydroxy-fl,fl-dimethyl butyramide and the reaction is carried outfor about 16 to 22 hours at the reflux temperature of the reactionmixture.

6. The process of claim 4 in which said racemic material is racemica-hydroxy-fi,fl-dimethyl-'y-butyrolactone and the reaction is carriedout for about 3 to 8 hours at the reflux temperature of the reactionmixture.

7. The process of claim 4 in which said racemization agent is present inan amount of from about 10% to 20% by weight of said racemic material.

8. The process of claim 4 in which said racemization agent is sodiummethoxide.

9. The process of claim 4 in which said racemization agent is aluminumisopropoxide.

10. The process of claim 4 in which said racemization agent is magnesiumisopropoxide.

11. A process for obtainingD(-)-a-hydroxy-fi,fl-dimethyl-'y-butyrolactone which comprises the stepsof bringing into contact with each other from about 1 to 1.1 mols ofl-brucine and a racemic material selected from the group consisting ofracemic a, -dihydroxy-,B,fldimethyl butyramide and racemica-hydroxy-B,Bdimethyl- 'y-butyrolactone in the presence of aracemization agent present in an amount of from about 3% to 26% byweight of said racemic material in the presence of methanol, recoveringfrom the reaction mixture a complex of l-brucine D)-ot-hydroxy-5,54imethyl-y-butyrolactonc, reacting said complex withsodium hydroxide thereby forming D(+)-sodium pantoate and treating saidD(+)- sodium pantoate with an acid thereby obtaining said D(-)-u-hydrow-3,5dimethyl-'y-butyrolactone, said racemization agent beingselected from the group consisting of alkali metal and alkaline earthmetal alcoholates in which the alcohol portion contains from one toabout four carbon atoms, aluminum isopropoxide, alkali metal silicatesand alkali metal carbonates.

12. The process of claim 11 which said reaction is carried out at atemperature of about 40 C. upto the reflux temperature of the reactionmixture.

13. A process for obtaining D()-a-hydroxy-p,p-dimethyl-'y-butyrolactonewhich comprises the steps of bringing from about 1 to 1.1 mols ofl-brucine and a racemic material selected from the group consisting ofracemic a,v-dihydroxy-B,;3-dimethyl butyramide and racemica-hydroxy-B,p-dimethyl-y-butyrolactone into contact with each other inmethanol at a temperature of from about 40 C. up to the refluxtemperature of the reaction mixture for a period of time from about 3 to48 hours in the presence of from about 3% to 26% by weight of saidracemic material of a racemization agent, recovering from the reactionmixture a complex of l brucine D()-a-hydroxy-fi,fl-dimethyl-y-butyrolactone, reacting said complex withsodium hydroxide thereby forming D(+) sodium pantoate and treating saidD(+) sodium pantoate with an acid thereby obtaining said,

D( )-a-hydroxy-p,B-dimethyl-ybutyrolactone, said racemization agentbeing selected from the group consisting of alkali metal and alkalineearth metal alcoholates in which the alcohol portion contains from oneto about four carbon atoms, aluminum isopropoxide, alkali metalsilicates and alkali metal carbonates.

14. The process of claim 13 in which said racemic material is racemica,'y-dihydroxy-fi,fl-dimethy1 butyramide and the reaction is carried outfor about 16 to 22 hours at the reflux temperature of the reactionmixture.

15. The process of claim 13 in which said racemic material is racemica-hydroxy-mfl-dimethyl-y-butyrolactone and the reaction is carried outfor about 3 to 8 hours at the reflux temperature of the reactionmixture.

16. The process of claim 13 in which racemization agent is present in anamount of from about to 20% by weight of said racemic material.

17. The process of claim 16 in which said racemization agent is sodiummethoxide.

18. The process of claim 16 in which said racemization agent is aluminumisopropoxide.

19. The process of claim 16 in which said racemization agent ismagnesium isopropoxide.

20. A process for obtaining a complex ofD()-ahydroxy-p,p-dimethyl-'y-butyrolactone and l-brucine which comprisesbringing at temperatures of from 40 C. up to the reflux temperature ofthe reaction mixture, a complex ofL(+)-a-hydroxy-p,fi-dimethyl-y-butyrolactone and l-brucine into contactwith from about 3% to 26% by weight, based on the weight of saidcomplex, of a racemization agent selected from the group consisting ofalkali metal and alkaline earth metal alcoholates in which the alcoholportion contains from one to about four carbon atoms, aluminumisopropoxide, alkali metal silicates and alkali metal carbonates.

21. The process of claim 20 in which said racemization agent is sodiummethylate.

22. A process for obtainingD()-a-hydroxy-fl,fl-dimethyl-'y-butyrolactone which comprises the stepsof bringing into contact with each other l-brucine and a racemicmaterial selected from the group consisting of racemic om-dihydroxy-;3,/3-dimethyl butyramide and racemicu-hydroxy-p,p-dimethyl-y-butyrolactone in methanol thereby forming acomplex of l-brucine D(-)-ahydroxy-pyp-dimethyl-'y-butyrolactone and acomplex of l-brucine L -a-hydroxy-fl,fl dimethyl-'y-butyrolactone,separating the complex of l-brucine D()-a-hydroxy-3,;3-dimethyl-y-butyrolactone, bringing into contact the remainingcomplex of l-brucine L(+)-a-hydroxy-fl,pdimethyl- -butyrolactone withfrom about 3% to about 26% by weight of said complex of a racemizationagent thereby forming l-brucine D()-a-hydroxy-fi,fi-dimethyl-'y-butyrolactone from said l-brucine L(+)-a-hydroxy- 5,B-dimethyl--butyrolactone and thereafter freeing from said l-brucineD()-a-hydroxy-p,fi-dimethyl-y-butyrolactone andD()-a-hydroxy-p,,6-dimethyl-'y-butyrolactone, said racemization agentbeing selected from the group consisting of alkali metal and alkalineearth metal alcoholates in which the alcohol portion contains from oneto about four carbon atoms, aluminum isopropoxide, alkali metalsilicates and alkali metal carbonates.

23. A process for obtaining a complex ofD(-)-a-hydroxy-tw-dimethyl-y-butyrolactone and l-brucine which comprisesbringing a complex of L(+)-a-hydroxy-p,pdimethyl- -butyrolactone andl-brucine into contact with a racemization agent selected from the groupconsisting of alkali metal and alkaline earth metal alcoholates in whichthe alcohol portion contains from one to about four carbon atoms,aluminum isopropoxide, alkali metal silicates and alkali metalcarbonates, said racemization agent being present in an amount of about3% to about 26% by weight of said complex.

References Cited in the file of this patent UNITED STATES PATENTS2,377,390 Weijlard et a1. June 5, 1945 FOREIGN PATENTS 605,444 GreatBritain July 23, 1948 626,498 Great Britain July 15, 1949 V v c UNITEDSTATES PATENT OFFICE CERTIFICATE CORRECTION Patent No. 2,967 869'January 10 1961 Charles O.- Beckmann et a1.

certified that error appears in the above numbered patie is hereby ndthat the said Letters Patent should read as ent requiring correction acorrected below Celumn 3 line' 58 for "It" read If column 10 line 6 for"and" read said Signed and sealed this 12th day of September 1961 CSEAL) Attest:

ERNEST W. SWIDER DAVID L. LADD Commissioner of Patents Attesting'OfficerY I USCOMM-DC

1. A PROCESS FOR OBTAINING D(-)-A-HYDROXY-B,B-DIMETHYL-Y-BUTYROLACTONEWHICH COMPRISES THE STEPS OF BRINGING INTO CONTACT WITH EACH OTHER1-BRUCINE AND A RACEMIC MATERIAL SELECTED FROM THE GROUP CONSISTING OFRACEMIC A,Y - DIHYDROXY - B,B-DIMETHYLBUTYRAMIDE AND RACEMICA-HYDROXY-B,B-DIMETHYL-Y-BUTYROLACTONE IN THE PRESENCE OF FROM ABOUT 3%TO ABOUT 26% BY WEIGHT OF SAID RACEMIC MATERIAL OF A RACEMIZATION AGENTIN METHANOL, RECOVERING FROM THE RESULTING REACTION PRODUCT A COMPLEX OF1-BRUCINE D(-)-A-HYDROXY-B,B-DIMETHYLY-BUTYROLACTONE AND FREEING FROMSAID COMPLEX SAID D(-)-A-HYDROXY-B,B-DIMETHYL-Y-BUTYROLACTONE, SAIDRACEMIZATION AGENT BEING SELECTED FROM THE GROUP CONSISTING OF ALKALIMETAL AND ALKALINE EARTH METAL ALCHOLATES IN WHICH THE ALCOHOL PORTIONCONTAINS FROM ONE TO ABOUT FOUR CARBON ATOMS, ALUMINUM ISOPROPOXIDE,ALKALI METAL SILICATES AND ALKALI METAL CARBONATES.